Abstract

Microenvironment-based alterations in phenotypes of mast cells influence the susceptibility to anaphylaxis, yet the mechanisms underlying proper maturation of mast cells toward an anaphylaxis-sensitive phenotype are incompletely understood. Here we report that PLA2G3, a mammalian homolog of anaphylactic bee venom phospholipase A2, regulates this process. PLA2G3 secreted from mast cells is coupled with fibroblastic lipocalin-type PGD2 synthase (L-PGDS) to provide PGD2, which facilitates mast-cell maturation via PGD2 receptor DP1. Mice lacking PLA2G3, L-PGDS or DP1, mast cell–deficient mice reconstituted with PLA2G3-null or DP1-null mast cells, or mast cells cultured with L-PGDS–ablated fibroblasts exhibited impaired maturation and anaphylaxis of mast cells. Thus, we describe a lipid-driven PLA2G3–L-PGDS–DP1 loop that drives mast cell maturation.

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Acknowledgements

We thank Y. Tanoue, H. Ohkubo, K. Araki and K. Yamamura for generating Ptges2−/− mice. This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (22116005 and 24390021 to M.M. and 23790119 and 24117724 to Y.T.), Promoting Individual Research to Nurture the Seeds of Future Innovation and Organizing Unique Innovative Network (PRESTO) of Japan Science and Technology Agency (to M.M.), and the Uehara, Mitsubishi, Terumo, Mochida and Toray Science Foundations (to M.M.).

Author information

Affiliations

  1. Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

    • Yoshitaka Taketomi
    • , Noriko Ueno
    • , Takumi Kojima
    • , Hiroyasu Sato
    • , Remi Murase
    • , Kei Yamamoto
    •  & Makoto Murakami
  2. School of Pharmacy, Showa University, Tokyo, Japan.

    • Yoshitaka Taketomi
    • , Hiroyasu Sato
    • , Remi Murase
    • , Momoko Kawana
    •  & Shuntaro Hara
  3. Department of Immunobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

    • Satoshi Tanaka
  4. School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Hyogo, Japan.

    • Mariko Sakanaka
  5. School of Dentistry, Showa University, Tokyo, Japan.

    • Masanori Nakamura
  6. Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

    • Yasumasa Nishito
  7. Department of Dermatology, Chiba University Graduate School of Medicine, Chiba, Japan.

    • Naotomo Kambe
  8. Institute for Advanced Biosciences, Keio University, Yamagata, Japan.

    • Kazutaka Ikeda
  9. College of Life and Health Sciences, Chubu University, Aichi, Japan.

    • Ryo Taguchi
  10. Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

    • Satoshi Nakamizo
    •  & Kenji Kabashima
  11. Departments of Chemistry and Biochemistry, University of Washington, Washington, USA.

    • Michael H Gelb
  12. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

    • Makoto Arita
  13. Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan.

    • Takehiko Yokomizo
  14. Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

    • Motonao Nakamura
    •  & Takao Shimizu
  15. Department of Nutrition, Koshien University, Hyogo, Japan.

    • Kikuko Watanabe
  16. Department of Advanced Medicine and Development, Bio Medical Laboratories, Saitama, Japan.

    • Hiroyuki Hirai
  17. Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo, Japan.

    • Masataka Nakamura
  18. Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Science, Tokyo, Japan.

    • Yoshimichi Okayama
    •  & Chisei Ra
  19. Department of Molecular Bihavioral Biology, Osaka Bioscience Institute, Osaka, Japan.

    • Kosuke Aritake
    •  & Yoshihiro Urade
  20. Department of Pharmaceutical Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.

    • Kazushi Morimoto
    •  & Yukihiko Sugimoto
  21. Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

    • Shuh Narumiya

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Contributions

Y.T. performed experiments and together with M.M. conceived and designed the study, interpreted the findings and wrote the manuscript; N.U., T.K., M.K., R.M. and H.S. performed experiments; S.T., M.S., Masanori Nakamura, Y.N., K.I., K.M., Satoshi Nakamizo, K.K., Y.O. and C.R. helped perform some experiments; K.Y., N.K., R.T., M.H.G. M.A., T.Y., Masataka Nakamura, K.W., H.H., Motonao Nakamura, K.A., Y.U., Y.S., T.S., Shu Narumiya and S.H. contributed to experimental designs.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Makoto Murakami.

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https://doi.org/10.1038/ni.2586

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